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Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

In the post-pandemic COVID-19 period, human activities have returned to normal and COVID-19 cases are usually mild. However, patients with multiple myeloma (MM) present an increased risk for breakthrough infections and severe COVID-19 outcomes, including hospitalization and death. The European Myeloma Network has provided an expert consensus to guide patient management in this era. Vaccination with variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4/5 strains, is essential as novel strains emerge and become dominant in the community. Boosters should be administered every 6–12 months after the last vaccine shot or documented COVID-19 infection (hybrid immunity). Booster shots seem to overcome the negative effect of anti-CD38 monoclonal antibodies on humoral responses; however, anti-BCMA treatment remains an adverse predictive factor for humoral immune response. Evaluation of the immune response after vaccination may identify a particularly vulnerable subset of patients who may need additional boosters, prophylactic therapies and prevention measures. Pre-exposure prophylaxis with tixagevimab/cilgavimab is not effective against the new dominant variants and thus is no longer recommended. Oral antivirals (nirmatrelvir/ritonavir and molnupiravir) and remdesivir are effective against Omicron subvariants BA.2.12.1, BA.4, BA.5, BQ.1.1 and/or XBB.1.5 and should be administered in MM patients at the time of a positive COVID-19 test or within 5 days post symptoms onset. Convalescent plasma seems to have low value in the post-pandemic era. Prevention measures during SARS-CoV-2 outbreaks, including mask wearing and avoiding crowded places, seem prudent to continue for MM patients. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Acute leukemia is the most common cancer in childhood; in particular, acute lymphoblastic leukemia (ALL) represents roughly up to 80% of all cases of acute leukemias in children. Survival of children with ALL has dramatically improved over the last few decades, and is now over 90% (versus 40% of adult patients) in developed countries, except for in infants (i.e., children < 1 year), where no significant improvement was registered. Philadelphia positive ALL (Ph+ALL) accounts for around 3% of cases of childhood ALL, its incidence increasing with patient’s age. Before the era of tyrosine-kinase inhibitors (TKIs), pediatric Ph+ALL showed a worse prognosis in comparison to other forms of ALL, and was managed with intensive chemotherapy, followed, whenever possible, by allogenic hematopoietic stem cell transplantation (HSCT) in first morphological complete remission. TKIs have revolutionized the current clinical approach, which involves combinations of imatinib plus standard chemotherapy that can abrogate the negative prognostic impact conferred by the presence of BCR/ABL1 rearrangement, resulting in the probability of event-free survival (EFS) being significantly better than that recorded in the pre-TKI era. Long-term follow-up confirms these data, questioning the role of a real advantage offered by HSCT over intensive chemotherapy plus TKI in all Ph+ALL pediatric patients. Imatinib was the first generation TKI and the prototype of targeted therapy, but over the years second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs showed a capacity to overcome resistance to imatinib in Ph+ hematological neoplasms. Given the effectiveness of the first-in-class TKI, imatinib, also the second-generation TKI dasatinib was incorporated in the treatment regimens of Ph+ALL. In this manuscript, we will discuss the role of this drug in pediatric Ph+ALL, analyzing the available data published to date.